Targeting alternate lactate energy source of breast tumors

Glucose levels are usually extremely low (<1 mM) within solid tumors. This implies that solid tumors are likely to be in a constant state of metabolic stress, and they must have the ability to adapt to alterations in glucose availability. Interestingly, intratumoral levels of lactate (5–10 mM) are much higher than glucose in many different tumor types. The potential significance of this observation has been highlighted in recent studies which demonstrated that lactate produced by glycolytic cells within the hypoxic regions of tumors, or by cancer associated fibroblasts, can be taken up by cells in more oxygenated regions of the tumor where it is further oxidized to produce ATP. These findings, as well as the results of additional studies, have highlighted the importance of functional mitochondria in cancer pathogenesis.

Under glucose replete conditions, most cancer cells are glycolytic and increases in the demand for ATP production can be met by enhancing glycolytic flux. However, the observations that glucose is generally limiting within tumors and that oxygen tension is both spatially and temporally dynamic suggests that the ability to engage mitochondria for energy production in tumors are also likely to be important. Indeed, accumulating evidence suggests that cancer cells utilize both glycolysis and mitochondrial oxidative metabolism to satisfy their metabolic demands.

This conclusion would appear to be at odds with the observation that most cells within tumors are in regions of hypoxia where oxygen-dependent oxidative phosphorylation (OXPHOS) was assumed to be inactive. However, it has been shown that mitochondrial oxidative phosphorylation is active within cells located in environments with oxygen levels as low as 0.5%. This suggests that even within hypoxic regions of tumors complete oxidation of glucose (and lactate) are not only possible, but also are likely to be important for tumor cell viability.

The observation that mitochondria play a key role in tumorigenesis has driven efforts to identify cancer chemotherapeutics that function by targeting oxidative metabolism. Notable is the interest in the potential anticancer activities of metformin, a widely prescribed antidiabetic drug that can inhibit complex I within the mitochondrial electron transport chain (ETC). Notwithstanding the potential utility of metformin in cancer, there is a need for additional therapeutics that interfere with mitochondrial function in a manner that minimizes the impact on normal cells. The estrogen-related receptor alpha (ERRα), a druggable transcription factor that regulates mitochondrial biogenesis and function, is thus a potentially useful therapeutic target.

ERRα is expressed in most cancers and increased activity of this receptor is associated with a negative outcome in breast and ovarian cancers. This transcription factor has been shown to be involved in mitochondrial biogenesis and in the regulation of OXPHOS. Given the restricted nature of its expression, and the subtle phenotypes in animals in which this receptor is ablated, authors considered that inhibition of its activity would enable a selective disruption of mitochondrial function in cancer.

In this study, it is demonstrated that the ability of breast cancer cells to oxidize lactate is essential for viability under conditions of glucose deprivation and that this activity confers resistance to PI3K/mTOR inhibitors. The nuclear receptor, estrogen-related receptor alpha (ERRα), was shown to regulate the expression of genes required for lactate utilization, and the analysis revealed that genetic or pharmacological inhibition of ERRα activity compromised lactate oxidation.

It was further demonstrated that most breast cancer cells that actively engage OXPHOS are insensitive to the inhibitory effects of PI3K/mTOR inhibitors, but that the efficacy of these targeted therapies can be enhanced by coadministration of an ERRα antagonist.

The clinical utility of PI3K inhibitors has been restricted by their dose limiting toxicities. Thus, it was significant that authors could show in vivo that the effective dose of select PI3K inhibitors could be reduced using drug regimens that included an ERRα antagonist.